Release of glutamate and activation of ionotropic glutamate receptors have been strongly implicated in the pathobiology of post-traumatic CNS injury. The role of metabotropic glutamate receptors (mGluR) has been less well studied. Using both in vivo and in vitro trauma models, we have acquired strong evidence that activation of group I mGluR contributes to neuronal necrosis. We have also demonstrated that among group I mGIuR, mGluRl but not mGluR5 activation, exacerbates post-traumatic neuronal injury. Moreover, recent data indicate that activation of both mGluRl and mGIuR5 may attenuate neuronal apoptosis in vitro. Elucidation of the mechanisms involved in these modulatory actions can provide a better understanding of glutamatergic processes involved in secondary neuronal injury, as well as a potential basis for novel treatment strategies. The proposed studies are intended to extend our initial findings by addressing the following hypotheses: (1) activation of mGluR1 contributes to post-traumatic neuronal necrosis by multiple mechanisms that include enhancing the activity of NMDA receptors, modulating Ca2+ channels in a direction favoring necrosis, potentiating the release of arachidonic acid, upregulating cyclic AMP, and stimulating the activation of calpain; (2) activation of either mGluR1 or mGluR5 attenuates neuronal apoptosis, both post-traumatic and biochemically induced, by inhibiting the intrinsic caspase cascade; (3) injury alters expression of mGluR1 and mGluR5 in a cell type specific fashion; and (4) activation of group I mGluR alters cellular bioenergetic state and associated magnesium homeostasis after traumatic brain injury (TBI), in part by modulating NMDA receptors. The Specific Aims propose to address these hypotheses by: (1) delineating potential mechanisms of group I mGluR mediated neurotoxicity, including assessment of the relative contributions of modulation of NMDA receptors, Ca2+ channels, arachidonic acid release, cAMP, and calpain activation; and comparing the relative roles of mGluRl and mGluR5 in this process; (2) examining mechanisms by which activation of group I mGluR inhibits neuronal cell death, and comparing the relative effects of mGluR1 and mGluR5 in this regard; (3) evaluating the effects of injury on cell type-specific alterations in mGluR1 and mGluR5 expression, receptor activity, and cell-cell interactions after neuronal injury; (4) determining the effects of group I mGluR modulation on cellular bioenergetics and intracellular free magnesium concentration after TBI, their relationship to subsequent cell death, and the extent to which this is mediated through modulation of NMDA receptors.